As a pediatric hematology/oncology fellow in training, I am committed to a career in academic medicine an want to contribute to the scientific advancement of the field. My long term objective is to understand the biologic mechanisms of mutagenesis and carcinogenesis by examining the importance of various components that maintain DNA replication fidelity. This may provide nw insights into the origin of genetic diseases and lead to novel therapeutic approaches for diseases such as cancer. The accumulation of mutations and loss of genomic integrity are the hallmarks of a cell's transformation from normal to neoplastic. Genetic integrity requires faithful DNA replication and immediate repair of spontaneous replication errors. Faithful replication is preserved by the DNA polymerase's ability to precisely pair complementary bases, its proofreading capacity to recognize and remove base pairing errors, and the mismatch repair systems proficiency in removing errors that escape the replication machinery. I hypothesize that the proofreading function cDNA polymerases delta and epsilon are critical for genomic stability and disruption of that function leads to a accumulation of mutations ultimately contributing to carcinogenesis. To test this hypothesis I propose to: (1) Clone the exonuclease coding domains of polymerases delta and epsilon. (2) Generate a mutation that specifically disrupt the exonuclease function while preserving the replicative capacity of the polymerases. (3) Study the defective gene in a cellular model and determine the effect on mutagenesis. (4) Introduce the defective genes into mice using homologous recombination technology and determine the effect on mutagenesis and carcinogenesis. This project will be guided by the dedicated mentorship of Dr. Bradley Preston , a recognized leader in the field of mutagenesis. The research will be conducted in the Eccles Institute of Human Genetics which houses community of scientists with expertise in molecular biology. It is within this environment of tremendous intellectual and technical support that i will develop the knowledge base and learn the tools of biomedical research necessary t succeed as a physician-scientist.